tbuckley/cabot-search huggingface dataset:
Comprehensive profiling of cancer associated cells in the blood of breast cancer patients to predict pathological complete response.
Authors: Adity A. Pore, Chathurika S. Dhanasekara, Hunaiz Bin Navaid, Siva A. Vanapalli, Rakhshanda Layeequr Rahman
Journal: Journal of Clinical Oncology (2022)

e12603 Background: Goal of neoadjuvant chemotherapy (NAC) has expanded from increasing the rate of breast conservation to in vivo assessment of response for use of second line therapies that increase survival. Pathological complete response (pCR) is a desirable goal of NAC; however, prediction of pCR for individualized therapeutic decisions remains a vexing problem. Cancer associated cells in the blood provide a promising venue to research response to therapy. Circulating tumor cells (CTCs) are of epithelial origin [CTCs (E+)] that undergo epithelial to mesenchymal transition [CTCs (E+M+)] to become motile and invasive; leading to fully invasive mesenchymal [CTCs (M+)] cells that seed in distant organs, causing metastasis. In addition, cancer associated macrophage-like cells (CAMLs) in the blood of cancer patients are reported to either engulf or aid the transport of cancer cells to distant organs. A comprehensive evaluation of these cancer associated circulating cells through liquid biopsy has a potential to provide a much needed biomarker to predict pCR. Methods: Patients treated with NAC with an intention to cure were enrolled in the study. Blood was collected at 3 time points: pre, mid and post NAC. Microfluidics-based label-free Labyrinth technology was used to isolate CTCs and CAMLs from the blood. Data was collected for patient demographics, biological tumor markers, and treatment response from medical records including pathology reports. Residual Cancer Burden Index (RCBI) and class (pCR vs. residual disease) were analyzed as dependent variables. Independent variables included CTCs, CAMLs and tumor receptor status for univariate and multivariate models to assess the combined effects using R. Results: A total of 57 samples from 19 patients were analyzed. Univariate regression models predicting RCBI or pCR using CTCs and CAML did not show any significant associations. However, in multivariate regression analysis predicting RCBI, an increase in post-NAC CAML and a decrease in post-NAC CTCs were associated with a decrease in RCBI (p=0.005, p=0.035, respectively). In a multivariate logistic regression model predicting pCR, CAML was positively associated with the log-odds of pCR (OR=1.60 [1.01, 2.54]; p=0.047), while CTCs showed a trend in negatively predicting pCR (OR=0.33 [0.10, 1.06]; p=0.063). When controlled for each other, increased CAML and decreased CTCs were associated with increased pCR. While increased M+ was associated with the decreasing log-odds of pCR (OR=0.27 [0.08, 0.99]; p=0.049), neither E+ nor E+M+ was associated with pCR. Conclusions: Increased CAMLs in circulation after treatment combined with lowered CTCs are associated with pCR and lower RCBI. M+ cells could be a factor governing association between CTCs and pCR.
The disproportionate burden of cancer associated with social behaviors in young women in the United States.
Authors: Caitlin Ruth Johnson, Cheng-I Liao, Ava Chan, Chunqiao Tian, Kathleen M. Darcy, Daniel Stuart Kapp, John K Chan
Journal: Journal of Clinical Oncology (2022)

10575 Background: To evaluate the incidences and trends of social determinant risk factor-associated cancers in the United States from 2001 to 2018. Methods: Social determinant risk factor-associated cancers, as classified by the CDC, were included: obesity, alcohol, tobacco, physical inactivity, and human papillomavirus (HPV). Data was obtained from the United States Cancer Statistics program from 2001-2018. SEER*Stat 8.3.9.2 and Joinpoint regression program 4.9.0.0 were used to calculate incidences and trends of cancers per 100,000. The age-adjusted incidence (AAI) was adjusted by the US 2000 standard population. Results: Over the 17-year study period, a total of 28,175,859 cancers were identified. Of these, 51.4% developed in men and 48.6% in women. Over 65.8% were risk factor-associated cancers and 34.2% were unrelated to these factors. Of note, over 60.1% of risk factor-related cancers developed in women compared to 39.9% in men. Although the incidence of risk factor associated cancers did not significantly change at 413.2/100,000 in women, this incidence decreased by 1.15% annually ( P&lt; 0.001). The age-specific incidences decreased in older (&gt; 50 years) men and women. Of the younger (20-45 years) group, these risk factor-associated cancers increased from 91.5 to 97.3/100,000 with an annual increase of 0.4% ( P&lt; 0.001) in younger women; there was no change for younger men on trend analyses over the study period. Conclusions: Over 65% of cancers in the US were associated with social determinants of health. There is a disproportionate burden of risk factor-associated cancers in women with increasing rates in younger age groups. Further research is needed to better understand the rationale of these important trends.
SMARCE1 deficiency generates a targetable mSWI/SNF dependency in clear cell meningioma
Authors: Roodolph St. Pierre, Clayton K. Collings, Daniel D. Samé Guerra, Christian J. Widmer, Olubusayo Bolonduro, Nazar Mashtalir, Akshay Sankar, Yu Liang, Wenya Linda Bi, Erica H. Gerkes, Vijaya Ramesh, Jun Qi, Miriam J. Smith, David M. Meredith, Cigall Kadoch
Journal: Nature Genetics (2022)
External validation of machine learning models for prediction of survival in undifferentiated pleomorphic sarcoma.
Authors: Linus Lee, Thomas Yi, Michael Fice, Conor Jones, Evan Klein, Neil Buac, Nicolas Lopez-Hisijos, Matthew W. Colman, Steven Gitelis, Alan T. Blank
Journal: Journal of Clinical Oncology (2022)

e13551 Background: Machine learning (ML) algorithms to predict cancer survival have recently been reported for a number of sarcoma subtypes, but none have investigated undifferentiated pleomorphic sarcoma (UPS). ML is a powerful tool that has the potential to better prognosticate UPS. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was queried from 2004 to 2015 for cases of histologically confirmed undifferentiated pleomorphic sarcoma (UPS) and malignant fibrous histiocytoma (MFH). Patient, tumor, and treatment characteristics were recorded, and various machine learning (ML) models were built to predict 1-, 3-, and 5-year survival. The best performing ML models were externally validated using an institutional cohort of UPS patients. Results: All ML models performed best at the 1-year time point and worst at the 5-year time point. On internal validation within the SEER cohort, the best models had c-statistics of 0.71 to 0.73 at the 5-year time point. Similarly, all ML models performed best at 1-year and worst at 5-year on external validation. The best performing models had c-statistics of 0.81 at the 5-year time point on external validation, demonstrating good performance in survival prediction. Conclusions: Machine learning models perform well for survival prediction in UPS, though this sarcoma subtype may be more difficult to prognosticate than other subtypes. Future studies are needed to further validate the machine learning approach for UPS prognostication. [Table: see text]
LGG-29. Use of Bevacizumab in Pediatric Low-grade Glioma: Ten-year experience in a single center
Authors: Margarida Simão Rafael, Ofelia Cruz, Sara Perez-Jaume, Vicente Santa-María, Cinzia Lavarino, Hector Salvador, Jordi Muchart, Jose Hinojosa, Mariona Suñol, Andrés Morales
Journal: Neuro-Oncology (2022)

Abstract PURPOSE: Pediatric low-grade gliomas (PLGG) have excellent overall survival but frequently need non-surgical therapy at diagnosis or after progression at unresectable sites such as the optic pathway. Chemotherapy side effects have led to the need for better-tolerated regimens with a sustained response. Bevacizumab, a humanized anti-VEGF monoclonal antibody has been used in monotherapy and/or in combination for these entities. Here we present our experience with its use in PLGG. METHODS: A retrospective, observational, single-institution study between 2008-2018 was performed, reporting the short-term outcomes of safety and efficacy of bevacizumab in progressive PLGG. RESULTS: Twenty-six patients with a median age at diagnosis of 3.32 years old [0.12-14.7] and the median age at the treatment of 8.11 years old [0.41-16.82] were included in the study. Nineteen had optic pathway gliomas and chiasmatic-hypothalamic gliomas (73.1%), 9 of them (47.4%) associated with neurofibromatosis type 1 (NF1). Fourteen non-NF1 tumors were molecularly studied, disclosing BRAF-KIAA1549 fusion transcript in 9 and BRAF V600E mutation in 2. Bevacizumab was administered in combination with other agent(s) in 16 of the 35 treatment courses. Responses were assessed at 3, 6, 12 months, and at the end of treatment. Progression-free survival at 12 months was 94%, and no severe adverse events were observed. CONCLUSIONS: In our series, Bevacizumab in PLGG showed short-term clinical efficacy with a favorable toxicity profile. Larger and long-term prospective studies may determine whether the response is conditioned upon different clinical or molecular features.
INSP-10. Minimal residual disease monitoring for pediatric brain tumors using ctDNA whole genome sequencing: opportunities and challenges
Authors: Matija Snuderl
Journal: Neuro-Oncology (2022)

Abstract Liquid biopsy offers a noninvasive approach to monitor cancer burden during therapy and surveillance. However, in pediatric brain cancers, liquid biopsy methods from the blood have been unsuccessful due to a low tumor burden and low number of mutations in coding regions. In contrast with targeted panels, whole genome sequencing (WGS)-derived patient specific mutational signature from a matched tumor-normal WGS can provide a personalized, highly specific approach to detect mutations in circulating cell free tumor DNA (ctDNA) and provide blood-based monitoring in pediatric patients with high sensitivity. Furthermore, it can be performed on lower amount of peripheral blood since WGS requires less depth compared to targeted ctDNA panels. We have profiled a diverse cohort of brain tumors including medulloblastomas, ependymomas, low- and high-grade gliomas. Using WGS of matched tumor-normal and plasma samples, we could derive a personalized mutational pattern and used an AI-based error suppression model for quantification and ultra-sensitive detection of ctDNA in plasma samples. A patient-specific personalized genome-wide compendium of somatic mutations could be established across all tumor types and ctDNA tested at the time of diagnosis, during the therapy or surveillance period. An AI-based error suppression model is implemented to filter out the noise in the cell free DNA (cfDNA) while the personalized mutational signature was used to detect the ctDNA in the cfDNA and to amplify the somatic signal contained in it. The ctDNA Tumor Fraction (TF) is compared to the clinical status and MR-based imaging. All subtypes of pediatric brain tumors contain sufficient number of mutations to derive personalized signatures and corelate with the clinical status. Patient-specific WGS tumor signature in ctDNA from blood can be used for sensitive monitoring of children with brain tumors. However, correlation between ctDNA levels and therapeutic response need to be established for various subtypes of brain tumors.
Potential role of STAG1 mutations in genetic predisposition to childhood hematological malignancies
Authors: Claudia Saitta, Stefano Rebellato, Laura Rachele Bettini, Giovanni Giudici, Nicolò Panini, Eugenio Erba, Valentina Massa, Franziska Auer, Ulrike Friedrich, Julia Hauer, Andrea Biondi, Grazia Fazio, Giovanni Cazzaniga
Journal: Blood Cancer Journal (2022)
RNA exosome drives early B cell development via noncoding RNA processing mechanisms
Authors: Brice Laffleur, Carolina R. Batista, Wanwei Zhang, Junghyun Lim, Biao Yang, Delphine Rossille, Lijing Wu, Jerson Estrella, Gerson Rothschild, Evangelos Pefanis, Uttiya Basu
Journal: Science Immunology (2022)

B cell development is linked to successful V(D)J recombination, allowing B cell receptor expression and ultimately antibody secretion for adaptive immunity. Germline noncoding RNAs (ncRNAs) are produced at immunoglobulin (Ig) loci during V(D)J recombination, but their function and posttranscriptional regulation are incompletely understood. Patients with trichohepatoenteric syndrome, characterized by RNA exosome pathway component mutations, exhibit lymphopenia, thus demonstrating the importance of ncRNA surveillance in B cell development in humans. To understand the role of RNA exosome in early B cell development in greater detail, we generated mouse models harboring a B cell–specific cre allele ( Mb1 cre ), coupled to conditional inversion-deletion alleles of one RNA exosome core component ( Exosc3 ) or RNase catalytic subunits ( Exosc10 or Dis3 ). We noticed increased expression of RNA exosome subunits during V(D)J recombination, whereas a B cell developmental blockade at the pro–B cell stage was observed in the different knockout mice, overlapping with a lack of productive rearrangements of VDJ genes at the Ig heavy chain ( Igh ). This unsuccessful recombination prevented differentiation into pre–B cells, with accumulation of ncRNAs and up-regulation of the p53 pathway. Introduction of a prearranged Igh VDJ allele partly rescued the pre–B cell population in Dis3 -deficient cells, although V-J recombination defects were observed at Ig light chain kappa ( Ig κ), preventing subsequent B cell development. These observations demonstrated that the RNA exosome complex is important for Igh and Ig κ recombination and establish the relevance of RNA processing for optimal diversification at these loci during B cell development.
Association of early tumor growth rate and survival outcomes in first-line metastatic non–small cell lung cancer (mNSCLC).
Authors: Antonio Tito Fojo, Kevin Brown, Diederik J. Grootendorst, SRIVIDYA KOTAPATI, Matthew Fronheiser, Phuong Tran, Jasmine I. Rizzo, David Leung, Mariann Micsinai Balan, No Firstname Kald.Abdallah@Bms.Com, Binsheng Zhao, Lawrence Howard Schwartz
Journal: Journal of Clinical Oncology (2022)

9063 Background: Tumor growth rates ( g) estimated using imaging measurements, have been associated with overall survival (OS) and progression-free survival (PFS) in patients with mNSCLC, including those treated with first-line immunotherapy (1L IO) or chemotherapy (chemo). Here, we evaluated whether early g estimates within 18 weeks of first treatment dose are associated with survival outcomes for 1L treatment in mNSCLC. Methods: This was a retrospective analysis of data from patients randomized to either nivolumab+ipilimumab (NIVO+IPI) or chemo in CheckMate 227 Part 1 (NCT02477826), or NIVO+IPI+chemo or chemo alone in CheckMate 9LA (NCT03215706). Tumor assessments were performed by blinded independent central review using RECIST v 1.1 at baseline, every 6 weeks for the first 48 weeks and then every 12 weeks until disease progression. The analysis included patients with at least 3 measurable timepoints, including baseline, week 6, week 12, and/or week 18. If a patient did not have a week 18 measurement, the first three measurements alone were used. To derive the median early g, sum of longest diameters (SLD), based on baseline, weeks 6, 12 and/or 18 assessments, and time relative to baseline were fitted to the model defined by sum of exponential growth (g) and decay (d): SLD (t) = exp (–d x t) + exp (g x t) – 1. OS and PFS were estimated using Kaplan-Meier methodology. Results: In the two studies, 865/1166 (75%) of randomized patients in CheckMate 227 Part 1 and 562/719 (78%) in CheckMate 9LA had evaluable tumor growth rate data (Table). The median early g at weeks 12 and 18 was numerically lower for the IO-containing arm vs chemo arm in both studies (Table). Patients with lower growth rate at week 12 or week 18 ( g in first quartile [Q1]) had better OS relative to those with higher rate ( g in fourth quartile [Q4]) across all treatment arms (Table). A similar trend was observed for PFS. Conclusions: Early g estimates based on 2 or 3 post-baseline tumor assessment timepoints were associated with longer-term survival outcomes for 1L treatment of mNSCLC and could discern efficacy outcomes. These findings provide the foundation for further research, which may incorporate volumetric segmentations of measurable lesions and radiomic feature changes to further explore indicators of patient outcomes that could inform future clinical trials and clinical practice.[Table: see text]
Racial disparities in the clinical use of durvalumab for patients with stage III unresectable non–small cell lung cancer treated at Veterans Health Administration facilities.
Authors: Amanda Moore, Zohra Nooruddin, Kelly R Reveles, Paromita Datta, Lance Brannman, Ion Cotarla, Andrew Frankart, Tiernan Mulrooney, Xavier Jones, Christopher R Frei
Journal: Journal of Clinical Oncology (2022)

8526 Background: Evidence from the PACIFIC study and real-world data highlight the benefit of durvalumab in patients with stage III unresectable non-small cell lung cancer (UR-NSCLC). However, limited literature exists regarding disparities in durvalumab treatment patterns such as treatment initiation delays (TID), treatment interruptions (TI), number of doses, duration of therapy (DOT), adverse effects (AEs), and treatment discontinuation (TD) in minority populations. Methods: Patients with stage III UR-NSCLC and a self-reported racial identity of Black or White treated with durvalumab following chemoradiotherapy (CRT) at any Veterans Health Administration (VHA) facility from January 1, 2017 to June 30, 2020 were included. Patients were followed from their date of durvalumab initiation through the earliest of their last VHA visit, loss to follow up, death, or end of the study; therefore, all patients had the opportunity to be treated for 12 months. Patients were excluded if durvalumab therapy was ongoing at the end of the study. Patient charts were retrospectively reviewed for baseline characteristics and durvalumab treatment patterns including TID (&gt;42 days from end of CRT to durvalumab start), TI (&gt;28 days between doses), number of doses, DOT, AEs, and TD. Nominal variables were compared using chi-square/Fisher’s exact tests. Continuous variables were compared using Student’s t-tests/Wilcoxon Rank Sum tests. Results: Among 924 patients, Black patients were younger than White patients (median age 67 years [IQR, 63-71] vs. 70 years [IQR, 65-73]; p&lt;0.01), more likely to be current smokers (54% vs. 45%; p=0.03), with more chronic liver disease (22% vs. 9%; p&lt;0.01), but less COPD (63% vs. 72%; p=0.01). Black patients experienced more TI (25% vs. 18%; p=0.03) but TID, number of doses, DOT, and TD were similar between the groups. Black patients were less likely to have an immune-related AE (irAE) (28% vs. 36%; p=0.03) (and less pneumonitis (7% vs. 14%; p&lt;0.01)). Toxicity was the reason for TD in 12% of Black patients vs. 20% of White patients (p=0.01), with no other significant (α &lt; 0.05) differences in reported reasons for TID, TI, or TD between the groups. Conclusions: In this real-world study, Black patients experienced similar TID, number of doses, and DOT as White patients. Black patients were less likely to experience an irAE (including pneumonitis) but experienced more TI; TD were similar but more likely to be from toxicity for White patients. Future research is needed to validate these findings.[Table: see text]
HGG-34. Upfront Molecular Targeted Therapy for the Treatment of BRAF-mutant Pediatric High-Grade Glioma
Authors: Tom Rosenberg, Kee Kiat Yeo, Audrey Mauguen, Sanda Alexandrescu, Sanjay P Prabhu, Jessica W Tsai, Seth Malinowski, Mrinal Joshirao, Karishma Parikh, Sameer Farouk Sait, Marc K Rosenblum, Jamal K Benhamida, George Michaiel, Hung N Tran, Sonika Dahiya, Kara Kachurak, Gregory K Friedman, JulieI Krystal, Michael A Huang, Ashley S Margol, Karen D Wright, Dolly Aguilera, Tobey J MacDonald, Susan N Chi, Matthias A Karajannis
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: The prognosis for pediatric high-grade glioma (pHGG) is poor despite aggressive multi-modal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained. METHODS: We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF +/- MEK inhibitors as part of their initial therapy. RESULTS: Nineteen patients were identified, with a median age of 10.7 years (range: 1.8–20.3). Histologic diagnoses included HGG (n=6), glioblastoma (n=3), anaplastic ganglioglioma (n=4), diffuse midline glioma (n=3), high-grade neuroepithelial tumor (n=1), anaplastic astrocytoma (n=1), and anaplastic astroblastoma (n=1). Recurrent concomitant oncogenic alterations included CDKN2A/B loss, H3 K27M, as well as mutations in ATRX, EGFR and TERT. Eight patients received BRAF inhibitor monotherapy. Eleven patients received combination therapy with BRAF and MEK inhibitors. Most patients tolerated long-term treatment well with no grade 4–5 toxicities. Objective and durable imaging responses were seen in the majority of patients with measurable disease. At a median follow-up of 2.3 years (range,0.3–6.5), three-year progression-free (PFS) and overall survival (OS) for the cohort were 65% and 82%, respectively, and superior to a historical control cohort treated with conventional therapies. CONCLUSIONS: Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes observed compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Children’s Oncology Group ACNS1723 clinical trial.
Eruptive Xanthomas with Branching Projections
Authors: Jiaqiang Zhou, Hao Cheng
Journal: New England Journal of Medicine (2022)

A 34-year-old woman presented with a 4-year history of progressive skin lesions and 3-month history of weight loss. Physical examination showed a symmetric distribution of clusters of pink-yellow papules that merged into branching projections on the trunk, buttocks, and all four limbs.